Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS‐13

Abstract

Summary Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening disorder and plasma exchange (PEX) remains the primary treatment modality. Twenty‐five patients with acute refractory/relapsing idiopathic TTP received rituximab in conjunction with PEX because of progressive clinical disease or deterioration in laboratory parameters, despite intensive standard therapy. In relapsing TTP, rituximab was started if antibody to ADAMTS‐13 (a disintegrin and metalloproteinase with thrombospondin motif‐13) was demonstrated during previous episodes. All 25 patients attained complete clinical and laboratory remission in a median of 11 d after initiating rituximab. In 21 cases, ADAMTS‐13 activity was within the normal range following rituximab. Inhibitors were detected in 24/25 patients by mixing studies and/or immunoglobulin G (IgG) antibodies to ADAMTS‐13 pre‐rituximab. There was no evidence of inhibitors and/or IgG activity <10% in 23/25 patients following rituximab. In acute refractory cases, the median number of PEX pre‐rituximab and following the first rituximab infusion was 13 and 9, respectively. There have been no infectious complications, despite low CD 19 levels and no relapses. In patients with acute refractory/relapsing idiopathic TTP, rituximab appears to be a safe, effective, targeted therapy with a significant reduction in the requirement for PEX.

Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab

“…A median follow-up of nearly 50 months is reflecting the longest follow-up period after rituximab treatment reported to date. In 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 the existing literature patients treated with plasma exchange and rituximab have been followed for up to three years [17,18], however median follow-up is reported less than 11 months [12]. Longer follow-up is required for addressing possible long-term side effects of rituximab and the safety of this treatment procedure [24].…”

“…Using this regimen, although only a small number of patients have been reported worldwide, the majority of patients with refractory or relapsing TTP achieved complete remission with complete clinical and laboratory responses including normal ADAMTS13 level and disappearance of anti-ADAMTS13 antibodies [11]. In the reported cases, only 10% -13% of patients relapsed after rituximab treatment after a median follow-up of 11 months [17][18]. Especially when considering B-cell recovery nine to twelve months after rituximab application, data for longterm follow-up is required.…”

“…In case of plasmarefractory TTP, which is defined as persistent thrombocytopenia or lactate dehydrogenase elevation after a total of seven daily plasma exchange procedures, current guidelines advise to intensify plasma exchange and to add corticosteroids in patients not receiving immunosuppressive drugs [12]. Due to the autoimmune nature of acquired idiopathic TTP rituximab has been used as a second-line immunosuppressive intervention in TTP cases refractory to plasma exchange as well as in frequently relapsing patients [16][17][18][19]. According to treatment schedules in Non-Hodgkin's lymphoma, rituximab is mainly administered at doses of 375 mg/m 2 weekly for an average of 4 doses.…”

A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura

“…8,12 Microtiter plates were coated with rADAMTS13 (Baxter Bioscience), patient plasma was added and incubated for 1 hour, and any anti-ADAMTS13 IgG present was detected using anti-human globulin. A standard curve was prepared by diluting an index reference plasma in PBS/BSA to achieve 100%, 80%, 40%, 20%, 10%, 5%, and 0% concentrations.…”

“…4,5 In such refractory/relapsing TTP patients, further immunosuppressive therapy may be required, such as Ciclosporin, cyclophosphamide, or vincristine. Increasingly, rituximab is being reported for the treatment of acute acquired idiopathic TTP, [6][7][8] but only in small case series and anecdotal reports. We present the results of the first phase 2 trial of the use of rituximab, in conjunction with standard therapy (PEX and steroids) within 3 days of admission for acute TTP.…”